Molecular imaging techniques can provide detection, diagnoses, or tracking of pathological conditions, as well as insights into the underlying mechanisms of various diseases.1 While many such approaches target specific biomolecular markers of disease, a more general biochemical parameter of increasing interest is pH. Because mammalian energy metabolism results in the production of acids (e.g., lactic acid and CO2/H2CO3), the body must actively regulate pH in order to maintain normal healthy physiological conditions. Correspondingly, local variations (e.g., reductions) in extra- or intracellular pH can be associated with the heterogeneous blood flow and nutrient supply concomitant with a number of altered physiological states and pathological conditions, including injury, ischemia, and inflammation, as well as various cancers.2-7 
A number of magnetic resonance (MR) modalities using either endogenous8,9 or exogenous agents10-27 as a more complete, less-invasive alternative to microelectrode-based pH measurements.7 For example, increasingly elaborate exogenous agents have been developed that exploit pH-sensitive nuclear magnetic resonance (NMR) chemical shifts (e.g. 31P or 19F)10-16 chemical-exchange saturation transfer (CEST) effects,9,17-20 or Gadolinium (Gd)-based R1 relaxivity changes21-24 to spectrally probe or image pH variations. Golman and co-workers25,26 demonstrated the use of hyperpolarized 13C-bicarbonate for MRI pH mapping in vivo; while this approach avoids many aforementioned challenges, its application can be limited by the inherently short (10 s of sec) lifetime of the highly non-equilibrium nuclear spin magnetization induced by the dynamic nuclear polarization (DNP) process, and by its nature the approach requires specialized instrumentation and capabilities not generally available in hospitals and imaging clinics.
Superparamagnetic iron oxide nanoparticles (SPIONs) are a class of MRI contrast agents having high biological tolerability and large magnetic moments, giving rise to high (usually transverse) relaxivities (up to ˜102-103 mM−1·s−1 per Fe ion).1,28-34 SPIONs can be synthesized with surface modifications to improve aqueous solubility/stability, limit aggregation, or modulate biological uptake (see e.g. Refs.29,30). It has been reported that certain surface functionalizations improved the information content of the SPIONs' MR response by binding specific ions35 or biological molecules36, thereby targeting specific tissue types or altering the SPIONs' transverse relaxivities (e.g., via analyte-modulated aggregation) to yield molecular ‘switch’-based contrast.33,37 